This invention relates to new platinum complexes in which the platinum cation is coordinated to heterocyclic sulfur compounds as well as monofunctional or bidentate amines. It relates also to a method for using these complexes to treat neoplastic disease in mammals.
Platinum complexes have been known to inhibit cell division by antimitotic activity since 1965, (Rosenberg et al., Nature 205, 698 (1965)). Since that time many such complexes have been prepared and tested for anticancer activity in animal tumor screening systems, and one of the most effective complexes, cis-dichlorodiammine platinum (II) (cis-Platin) is used clinically for treatment of certain human tumors.
However, cis-Platin as well as other complexes of its type have toxic side effects which limit the therapeutic, dose. Morbidity in human patients include hematological, renal and neural (8th nerve) damage. See, e.g., Leh and Wolfe, J. Pharmaceut. Sci. 65, 315-328 (1976). For this reason there has been an effort to synthesize platinum complexes that are more active against tumor cells while having less toxicity.
The effects of substituents in platinum complexes are not well understood. Most complexes synthesized for testing in animal tumor systems have not differed substantially from the cis-Platin model. Such complexes are typically of the form: ##STR2## wherein A is a carrier ligand, typically a monodentate or bidentate amine and X is a leaving group, typically a chloride ion. The carrier ligand A is believed to promote the activity of the complex by facilitating its transport into the cell by means, for example, of favorable stearic factors, hydrophilic or lipophilic character or structural and electronic properties that promote binding to cell receptors.
The leaving groups are believed play a more direct role and their effectiveness is linked to the ease with which hydrolysis of the platinum-X bond can occur. Complexes of ligands that hydrolyze rapidly, such as NO.sub.3 - are highly toxic. Those that hydrolyze slowly, such as CN.sup.-, are generally inactive.
The most active complexes have halide or carboxylic leaving groups [Hydes, in Platinum Coordination Complexes in Cancer Chemotherapy, Hacker et al., (eds.) M. Nijhoff Publishing (1984)]. Novel complexes involving sulfur leaving groups have been infrequently investigated and these have usually been mondentate groups [Foye and Kaewchanslip, J. Pharmaceut. Sci. 68(9), 1131-1135 (1979)]; U.S. Pat. No. 4,578,491 (Amundsen, et al., 1986).
The present invention is directed to a new class of platinum complexes in which the platinum is coordinated to a bidentate heterocyclic sulfur-containing group. It is believed that these sulfur bonded complexes have a different spectrum of activity than the conventional cis-Platin analogues, and will offer clinical alternatives to cis-Platin chemotherapy. It is an object of the invention to provide a method for synthesizing heterocyclic sulfur complexes of platinum. Another object is to provide a method to use these complexes in the treatment of neoplastic disease in mammals.